The present invention relates to effervescent formulations which include the active substance dexketoprofen and which rapidly dissolve in water; and to a process for production of said effervescent formulations. The present invention also relates to pharmaceutical formulations including dexketoprofen which is used in symptomatic treatment of mild to moderate pains such as musculoskeletal pains, dysmenorrhoea, toothache, post-operative pains. Said formulations are characterized in being in effervescent form.
Dexketoprofen, named (+)-(S)-2-(3-Benzoylphenyl) propionic acid (Formula I), is the S (+) enantiomer of ketoprofen which is responsible for therapeutic effect. Nonetheless, it was disclosed that S (+) enantiomer of ketoprofen shows a quicker and stronger effect than racemic ketoprofen of the same amount (Sunshine et al., WO89/046558). Dexketoprofen or its pharmaceutically suitable salts are analgesic, anti-inflammatory, and antipyretic drugs belonging to the group of non-steroidal anti-inflammatory drugs.

Dexketoprofen is produced by Menarini as dexketoprofen tromethamine salt under the tradename Keral on the market. Dexketoprofen tromethamine salt was first disclosed in the European patent numbered EP0668851. In addition, said patent also discloses the production method, suitable dosage forms and indications of dexketoprofen tromethamine salt.
Dexketoprofen and its pharmaceutically acceptable salts are drugs used as antipyretic, analgesic and anti-inflammatory in treatment of mild and moderate pains like toothache, menstrual pain, post-operative pains and musculoskeletal pains. In the treatment of the said pains, dexketoprofen is desired to reach to peak plasma concentration quickly in order to relieve these pains rapidly. It widely depends on absorption of dexketoprofen in the gastrointestinal system in a short time after it is taken into the body.
Dexketoprofen is found in forms of 50 mg/2 ml injection solution, 25 mg film tablet, and 25 mg effervescent tablet on the market.
In order for active agents which are taken in solid oral dosage forms such as capsule, conventional tablet or film tablet to be absorbed; firstly, the said substance must completely dissolve in gastric juice. Moreover, the gastric juice amount affects the dissolution rate of the active substance and therefore the absorption rate. In the case that gastric juice amount is low, the dissolution rate of the active substance and also the absorption rate is declined. Dissolution of an organic acid derivative substance such as dexketoprofen in the gastric fluid before being absorbed in the digestive system pulls pH of the stomach down even more and this not only affects the dissolution rate and therefore the absorption of dexketoprofen, but also causes stomach problems because of contact of the active agent with the stomach for too long. Low absorption of dexketoprofen caused by its failure to dissolve in an efficient amount leads to low bioavailability, resulting in failure to perform an effective treatment.
As seen, formulations which can allow dissolution of dexketoprofen independent from gastric fluid and pH are needed in order to perform an effective treatment.
From another aspect, there is need for new formulations which can provide high absorption of dexketoprofen by enabling complete dissolution of the active agent dexketoprofen and therefore can provide high bioavailability; and for dosage forms which include these formulations.
It has also been seen that the surface of water turns yellow when effervescent formulations comprising dexketoprofen contact with water during its use and yellowing on water surface affects patients negatively during use of the drug. It has been observed that stability problems of said dexketoprofen formulations cause negative results such as yellowing on water surface during use as mentioned or some part of the drug comprising active agent is not dissolved. In that case, the patient can say that the treatment could not be provided effectively due to the problems observed during the use of effervescent formulations comprising dexketoprofen such as yellow formation in water and sediments of the drug which is not dissolved.
Accordingly, there is need to develop stable effervescent formulations which do not present problems in the prior art such as yellowing in water, remaining of some part of the active agent without dissolving and, in line with this, sedimentation of the drug on the bottom of the glass.